Precision Medicine for Dilated Cardiomyopathy-Cardiac Magnetic Resonance to Identify Early Family Phenotypes

扩张型心肌病精准医疗——心脏磁共振识别早期家族表型

• 批准号: 10204104
• 负责人: RAY E. HERSHBERGER
• 金额: $ 78.15万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10204104
• 关键词: Affect; African; Angiotensin-Converting Enzyme Inhibitors; Biological; Biology; Budgets; Cardiac; Characteristics; Clinical; Clinical Research; Data; Diagnostic; Diffuse; Dilatation - action; Dilated Cardiomyopathy; Disease; Echocardiography; Enrollment; European; Family; Family member; Fibrosis; First Degree Relative; Foundations; Functional disorder; Future; Gadolinium; Genes; Genetic; Genetic Risk; Genetic study; Guidelines; Heart failure; Individual; Infrastructure; Intervention; Knowledge; Left; Left Ventricular Dysfunction; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Myocardial; Myocardial tissue; Myocardium; Pathogenicity; Pathway interactions; Patients; Phenotype; Play; Practice Guidelines; Primary idiopathic dilated cardiomyopathy; Public Health; Race; Recording of previous events; Relative Risks; Risk; Risk Management; Role; Scanning; Site; Specific qualifier value; Structure; Symptoms; Testing; Tissues; Uncertain Risk; Variant; Ventricular; Work; advanced disease; age group; base; exome sequencing; high risk; inherited cardiomyopathy; innovation; interstitial; precision medicine; prevent; proband; prognostic value; rare variant; screening; serial imaging; sex; variant of unknown significance

Project Description Dilated cardiomyopathy of unknown cause (DCM) is a major public health problem affecting more than a million people in the U.S. Most DCM is now known to have an underlying genetic basis. First-degree relatives (FDRs) of an individual with DCM are considered to be genetically at risk, particularly if they carry variants classified as pathogenic (P), likely pathogenic (LP) or uncertain significance (VUS) in DCM genes. Practice guidelines recommend that these FDRs undergo serial imaging because prompt intervention may avert advanced disease. While tissue damage is already well underway when DCM is manifest, myocardial tissue changes, termed “pre- DCM” herein, are known to precede adverse changes in myocardial structure and function. Our central hypothesis states that cardiac magnetic resonance (CMR) imaging may detect pre-DCM in individuals with increased genetic risk by identifying myocardial tissue changes prior to myocardial structural and functional changes. CMR measures of myocardial tissue characteristics, including late gadolinium enhancement and myocardial T1 mapping, have been histopathologically validated and have established diagnostic and prognostic value in DCM. Thus, our specific hypotheses state that adverse CMR-based myocardial tissue characteristics will be associated with (1) A higher burden (number) of relevant variants (P, LP, VUS) in established DCM genes; and (2) Subsequent adverse changes in measures of cardiac structure and function. We propose to leverage the DCM Precision Medicine Study, a multisite DCM Consortium study now completing the enrollment of 1300 DCM patients (probands), balanced for race and sex, and their FDRs, most with no history of DCM. FDRs are cascade tested for relevant variants (P, LP, VUS) in DCM genes identified in probands. We aim to (1) Estimate the associations between CMR-based myocardial tissue characteristics and the number (burden) of the proband's variants in DCM genes in at-risk FDRs. In 650 FDRs of probands with LP/P variants and/or VUSs, CMR scans will be completed at 9 participating DCM Consortium sites. The association between CMR-based myocardial tissue characteristics and the number of the proband's variants of each class (LP/P, VUS) carried by an at-risk FDR in a particular age group will be evaluated, adjusting for biologically relevant covariates. We will also (2) Estimate the association between CMR-based myocardial tissue characteristics and subsequent changes in measures of cardiac structure and function in FDRs with normal baseline left-ventricular size and function. FDRs examined in Aim 1 with normal left ventricular size and systolic function will receive a second CMR exam 2.5 years after their baseline exam. We will estimate the covariate-adjusted associations between baseline myocardial tissue characteristics and subsequent changes in CMR-derived measures of cardiac structure and function in groups defined by the most deleterious of the proband's variants carried (none, VUS, or LP/P). This study will validate a CMR-derived “pre-DCM” phenotype for FDRs who carry P or LP variants (established risk), and also provide preliminary evidence that some VUSs are biologically relevant.

项目描述 原因不明的扩张型心肌病（DCM）是一个主要的公共卫生问题，影响超过一百万人 大多数DCM现在已知有潜在的遗传基础。一级亲属 患有DCM的个体被认为具有遗传风险，特别是如果他们携带分类为 DCM基因中的致病性（P）、可能致病性（LP）或不确定意义（VUS）。实践指南 建议这些FDR进行系列成像，因为及时干预可能会避免晚期疾病。 虽然当DCM明显时组织损伤已经进行得很好，但心肌组织变化，称为“前-后”， 本文中的“DCM”已知先于心肌结构和功能的不利变化。我们的中央 一种假设认为，心脏磁共振（CMR）成像可以检测患有前DCM的个体， 通过在心肌结构和功能之前识别心肌组织变化增加遗传风险 变化心肌组织特征的CMR测量，包括晚期钆增强和 心肌T1标测，已被组织病理学证实，并已建立诊断和预后 值以DCM表示。因此，我们的特定假设表明，不良的基于CMR的心肌组织特征 将与（1）在已建立的DCM基因中相关变体（P、LP、VUS）的较高负担（数量）相关; 以及（2）随后心脏结构和功能测量的不良变化。我们建议利用 DCM精准医学研究，一项多中心DCM联盟研究，目前已完成1300例入组 DCM患者（先证者），种族和性别平衡，以及他们的FDR，大多数没有DCM病史。FDR是 在先证者中鉴定的DCM基因中检测相关变体（P、LP、VUS）的级联反应。我们的目标是（1）估计 基于CMR的心肌组织特征与心肌细胞数量（负荷）之间的相关性 高危FDR中DCM基因的先证者变异。在650例LP/P变异和/或VUS先证者的FDR中， CMR扫描将在9个参与DCM联盟的研究中心完成。基于CMR的 心肌组织特征和先证者携带的各类（LP/P，VUS）变异数 将评估特定年龄组中的风险FDR，调整生物学相关协变量。我们将 （2）估计基于CMR的心肌组织特征与随后的 基线左心室大小正常的FDR中心脏结构和功能指标的变化， 功能在目标1中检查的左心室大小和收缩功能正常的FDR将接受第二次 CMR检查2.5年后，他们的基线检查。我们将估计协变量调整后的关联， 基线心肌组织特征和CMR衍生的心脏测量的后续变化 由先证者携带的最有害的变异体定义的组中的结构和功能（无，VUS， 或LP/P）。本研究将验证携带P或LP变体的FDR的CMR衍生的“前DCM”表型 （已确立的风险），并提供初步证据证明某些VUS具有生物学相关性。